Publications by authors named "Jung Hur"

31 Publications

Platycodin D attenuates airway inflammation via suppression Th2 transcription factor in a murine model of acute asthma.

J Asthma 2021 Jun 23:1-11. Epub 2021 Jun 23.

Division of Pulmonary, Allergy and Critical Care Medicine, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.

Bronchial asthma is a common chronic inflammatory condition of the airway tissue. Platycodin D (PLD) has antiinflammatory effects in a mouse model of allergic asthma. In this work, the anti-asthma potential of PLD was studied by investigation of its effect to suppress airway inflammation and mucin production, a murine model of asthma and the possible mechanisms. Mice were randomly assigned to five experimental groups: control, ovalbumin (OVA), OVA+ICS (intranasal fluticasone), OVA+PLD and OVA+PLD/ICS. Airway histological studies were evaluated by the H&E staining; IL-4, IL-5, and IL-13 in bronchoalveolar lavage fluid were evaluated by ELISA; GATA3 and IRF4 mRNA of airway were measured by RT-PCR and their protein level were measured by Western blotting. Our study showed that PLD suppressed eosinophilic inflammation and mucin production in bronchial mucosa. Moreover, PLD inhibited production of Th2 cytokines such as IL-4, IL-5, and IL-13. Protein production of GATA3 and IRF4, were also decreased in PLD treated OVA asthma model. Taken together, our results provided evidence that PLD inhibits the airway inflammation via suppression of Th2 transcription factor production. These findings suggest that PLD may effectively ameliorate the progression of asthma. These results suggest that PLD could be used as a therapy for allergic asthma.
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http://dx.doi.org/10.1080/02770903.2021.1941084DOI Listing
June 2021

MicroRNA-21 inhibition attenuates airway inflammation and remodelling by modulating the transforming growth factor β-Smad7 pathway.

Korean J Intern Med 2021 05 18;36(3):706-720. Epub 2021 Feb 18.

Division of Allergy and Pulmonary Medicine, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea.

Background/aims: Current asthma therapies remain unsatisfactory for controlling airway remodelling in asthma. MicroRNA-21 is a key player in asthma pathogenesis, but the molecular mechanisms underlying its effects on airway remodelling are not completely understood. We investigated the effects of inhibition of microRNA-21 on allergic airway inflammation and remodelling.

Methods: Female BALB/c mice were divided into four groups: control, ovalbumin-sensitized and -challenged for 3 months, microRNA-negative control-treated ovalbumin-treated, and microRNA-21 inhibitor-treated ovalbumin-treated groups. Parameters related to airway remodelling, cytokine production, airway inflammation, and airway hyperresponsiveness were compared between groups. Human bronchial smooth muscle cells were used in a mechanism study.

Results: In this asthma model, ovalbumin-sensitized and -challenged mice exhibited allergic airway inf lammation and airway remodelling. MicroRNA-21 inhibitor-treated mice had fewer inflammatory cells, lower TH2 cytokine production, and suppressed parameters related to remodelling such as goblet cell hyperplasia, collagen deposition, hydroxyproline content, and expression of smooth muscle actin. Inhibition of microRNA-21 decreased transforming growth factor β1 expression and induced Smad7 expression in lung tissue. In human bronchial smooth muscle cells stimulated with transforming growth factor β1, microRNA-21 inhibition upregulated Smad7 expression and decreased markers of airway remodelling.

Conclusion: Inhibition of microRNA-21 had both anti-inflammatory and anti-remodelling effects in this model of ovalbumin-induced chronic asthma. Our data suggest that the microRNA-21-transforming growth factor β1-Smad7 axis modulates the pathogenesis of ovalbumin-induced chronic asthma and in human bronchial smooth muscle cells. MicroRNA-21 inhibitors may be a novel therapeutic target in patients with allergic asthma, especially those with airway remodelling.
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http://dx.doi.org/10.3904/kjim.2020.132DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8137415PMC
May 2021

Glucagon-like peptide 1 receptor (GLP-1R) agonist relieved asthmatic airway inflammation via suppression of NLRP3 inflammasome activation in obese asthma mice model.

Pulm Pharmacol Ther 2021 04 12;67:102003. Epub 2021 Feb 12.

Division of Pulmonary, Allergy and Critical Care Medicine, Department of Internal Medicine, Seoul St Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea. Electronic address:

Background: Obesity is a correctable factor for uncontrolled bronchial asthma. However, the effects of glucagon-like peptide-1 receptor (GLP-1R) agonist, a recently approved antiobestic drug, on airway hyperresponsiveness (AHR) and immune responses are not known.

Methods: Mice were fed with high-fat diet (HFD, 60% fat) for 8 weeks to induce obesity. Ovalbumin (OVA) sensitization and challenges were performed for 7 weeks. The mice were injected intraperitoneally with GLP-1R agonist 5 times a week for 4 weeks after OVA sensitization. After AHR measurement, expression of Th2, Th17 cytokines, and interleukin (IL)-33 were measured in BALF and lung tissues. Moreover, IL-1β and activity level of nucleotide oligomerization domain-like receptor protein 3 (NLRP3) were analyzed to investigate the mechanism of GLP-1R agonist on asthmatic airway inflammation.

Results: HFD induced significant weight gain, OVA sensitization and challenge in obese mice made eosinophilic airway inflammation, and increased AHR. Treatment with GLP-1R agonist-induced weight loss suppressed eosinophilic airway inflammation and decreased AHR. Expression of IL-4, 5, and 33 was increased in BALF of obese asthma mice followed by a decrease in response to GLP-1R agonist treatment. Moreover, lung tissue H&E stain revealed that peribronchial inflammation induced by obesity and OVA was effectively suppressed by GLP-1R agonist. Expressions of NLRP3, activated caspase-1, and IL-1β were increased in lung tissues of obese asthma mice and demonstrated a decrease in response to GLP-1R agonist treatment.

Conclusions: GLP-1R agonist effectively induced weight loss, suppressed eosinophilic bronchial airway inflammation, and AHR in obese asthma mice. These effects were mediated by suppression of NLRP3 inflammasome activity and IL-1β. GLP-1R agonist is proposed as a novel anti-asthmatic agent targeting the obese asthmatics.
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http://dx.doi.org/10.1016/j.pupt.2021.102003DOI Listing
April 2021

MicroRNA-21 Inhibition Suppresses Alveolar M2 Macrophages in an Ovalbumin-Induced Allergic Asthma Mice Model.

Allergy Asthma Immunol Res 2021 Mar;13(2):312-329

Division of Allergy, Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea.

Purpose: MicroRNA-21 (miR-21) influences the Th2 immune pathway by suppressing the expressions of interleukin (IL)-12 and interferon (IFN)-γ. The effects of miR-21 suppression on alveolar macrophage polarization and airway inflammation are not known.

Methods: BALB/c and miR-21 knockout (KO) mice were sensitized and challenged with ovalbumin (OVA). The anti-miR-21 antagomir was administered to BALB/c mice by intranasal inhalation from the day of OVA sensitization. Changes in cell counts, cytokine levels in bronchoalveolar lavage fluid (BALF), and airway hyperresponsiveness (AHR) were examined. Total, M1, and M2 macrophages were examined in the lung tissues by immunohistochemistry (IHC). M2 macrophages from the OVA mice lung were inhaled into the anti-miR-21 antagomir-treated asthmatic mice. Moreover, the polarization of M0 to M2 macrophages upon IL-4 stimulation was analyzed after anti-miR-21 antagomir transfection.

Results: The miR-21 KO mice showed decreases in AHR, total cell and eosinophil counts in BALF, and in the levels of IL-4, IL-5, IL-10, and IL-13. Expression of IL-12 and IFN-γ were increased in the miR-21 KO mice. Peribronchial inflammation and goblet cell dysplasia were significantly decreased in the lung tissues of miR-21 KO OVA mice compared to the wild type OVA mice. IHC for M1, M2, and total macrophage in the lung tissues showed that miR-21 inhalation suppressed alveolar M2 macrophages in KO mice. M2 macrophage inhalation restored AHR and eosinophilic airway inflammation in the miR-21 antagomir-treated mice. Moreover, anti-miR-21 antagomir transfection decreased the expression of M2 markers and increased the expression of M1 markers in M0 macrophages after IL-4 stimulation.

Conclusions: The results suggest that miR-21 antagonism could suppress alveolar M2 macrophage polarization, decreasing not only the Th2 eosinophilic airway inflammation but also AHR and airway remodeling process.
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http://dx.doi.org/10.4168/aair.2021.13.2.312DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7840870PMC
March 2021

Intraoperative surveillance of the vertebral artery using indocyanine green angiography and Doppler sonography in craniovertebral junction surgeries.

Neurosurg Focus 2021 01;50(1):E5

5Department of Neurosurgery, Eunpyeong St. Mary's Hospital, The Catholic University of Korea, Seoul, Korea.

Objective: The authors sought to evaluate the usefulness of indocyanine green (ICG) angiography and Doppler sonography for monitoring the vertebral artery (VA) during craniovertebral junction (CVJ) surgery and compare the incidence of VA injury (VAI) between the groups with and without the monitoring of VA using ICG angiography and Doppler sonography.

Methods: In total, 344 consecutive patients enrolled who underwent CVJ surgery. Surgery was performed without intraoperative VA monitoring tools in 262 cases (control group) and with VA monitoring tools in 82 cases (monitoring group). The authors compared the incidence of VAI between groups. The procedure times of ICG angiography, change of VA flow velocity measured by Doppler sonography, and complication were investigated.

Results: There were 4 VAI cases in the control group, and the incidence of VAI was 1.5%. Meanwhile, there were no VAI cases in the monitoring group. The procedure time of ICG angiography was less than 5 minutes (mean [± SD] 4.6 ± 2.1 minutes) and VA flow velocity was 11.2 ± 4.5 cm/sec. There were several cases in which the surgical method had to be changed depending on the VA monitoring. The combined use of ICG angiography and Doppler sonography was useful not only to monitor VA patency but also to assess the quality of blood flow during CVJ surgery, especially in the high-risk group of patients.

Conclusions: The combined use of ICG angiography and Doppler sonography enables real-time intraoperative monitoring of the VA by detecting blood flow and flow velocity. As the arteries get closer, they provide auditory and visual feedback to the surgeon. This real-time image guidance could be a useful tool, especially for high-risk patients and inexperienced surgeons, to avoid iatrogenic VAI during any CVJ surgery.
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http://dx.doi.org/10.3171/2020.10.FOCUS20770DOI Listing
January 2021

Evaluation of Human MSCs Treatment Frequency on Airway Inflammation in a Mouse Model of Acute Asthma.

J Korean Med Sci 2020 Jun 15;35(23):e188. Epub 2020 Jun 15.

Division of Allergy and Pulmonary Medicine, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea.

Background: Studies in experimental models of allergic asthma have shown that mesenchymal stem cells (MSCs) have therapeutic potential for T-helper 2 (T2) cell-mediated inflammation. However, the mechanisms underlying these therapeutic effects are not fully understood and their safety has not been confirmed.

Methods: Using a mouse model of experimental allergic asthma, we investigated the efficacy of human adipose-derived mesenchymal stem cells (hADSCs) or human bone marrow-derived mesenchymal stem cells (hBMSCs) according to treatment frequency and timing.

Results: Ovalbumin (OVA)-sensitized and -challenged mice exhibited airway hyperresponsiveness (AHR), airway inflammation, and significant increases in T2 cytokine levels. Both double and single human mesenchymal stem cell (hMSC) treatments significantly decreased AHR and bronchoalveolar lavage fluid counts. In addition, single treatment with hMSCs showed significant attenuation of allergic airway inflammation. However, double treatment with hMSCs during OVA -sensitization and -challenge further increased inflammatory cell infiltration, and T2 cytokine levels.

Conclusion: The results of treatment with hADSCs or hBMSCs suppresses AHR and airway inflammation. However, double hMSC treatment significantly induces eosinophilic airway inflammation and lung histological changes. Therefore, double hMSC treatment is ineffective against asthma and single injection frequency appears to be more important for the treatment of asthma. These results suggest that hMSC therapy can be used for treatment of asthma patients but that it should be used carefully.
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http://dx.doi.org/10.3346/jkms.2020.35.e188DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7295606PMC
June 2020

Blockade of thymic stromal lymphopoietin and CRTH2 attenuates airway inflammation in a murine model of allergic asthma.

Korean J Intern Med 2020 05 19;35(3):619-629. Epub 2020 Mar 19.

Division of Allergy and Pulmonary Medicine, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea.

Background/aims: Thymic stromal lymphopoietin (TSLP) is an epithelial cell-derived cytokine that plays a key role in Th2-mediated inflammation, both directly by promoting the proliferation of naïve CD4 Th2 cells, and indirectly by activating dendritic cells (DCs). TSLP-activated DCs induce the expansion of chemoattractant receptor homologous molecule expressed on Th2 (CRTH2)+ CD4+ Th2 memory cells, which undergo a Th2 response and express prostaglandin D2 (PGD2) synthase. CRTH2, a PGD2 receptor, is a selective Th2-cell surface marker. We investigated the effects of an anti-TSLP antibody (Ab) and a CRTH2 antagonist, as well as their mechanisms of action, in a mouse model of acute asthma.

Methods: BALB/c mice were sensitized and challenged with ovalbumin. We then evaluated the effects of the administration of an anti-TSLP Ab either alone or together with a CRTH2 antagonist on cell counts, Th2 cytokine levels in bronchoalveolar fluid, and the levels of epithelium-derived cytokines such as TSLP, interleukin (IL) 33, and IL-25 in lung homogenates, as well as airway hyper-responsiveness (AHR).

Results: Anti-TSLP Ab and the CRTH2 antagonist significantly attenuated eosinophilic airway inflammation, AHR, and the expression of Th2 cytokines. The expression of GATA-3 and the levels of IL-33 and IL-25 in lung tissues were affected by the combined anti-TSLP and CRTH2 antagonist treatment.

Conclusion: These results suggest that the dual blockade of TSLP and CRTH2 may serve as an effective treatment target for eosinophilic asthma.
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http://dx.doi.org/10.3904/kjim.2018.248DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7214371PMC
May 2020

Pravastatin alleviates allergic airway inflammation in obesity-related asthma mouse model.

Exp Lung Res 2019 Nov - Dec;45(9-10):275-287. Epub 2019 Oct 12.

Division of Allergy, Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul St Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.

Obesity is one of the factors associated with severe, uncontrolled asthma. The effect of pravastatin on asthmatic airway inflammation in obesity has not been evaluated. C57BL/6 mice were fed a high-fat diet (HFD) to induce obesity with or without ovalbumin (OVA) sensitization and challenge. Pravastatin was administered intraperitoneally during the OVA treatment. Airway inflammation and airway hyper-responsiveness (AHR) were analyzed and lung tissues were examined. The changes in mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K)/Akt signaling pathways were measured in the lung tissues. HFD with OVA sensitization and challenge exacerbated eosinophilic and neutrophilic airway inflammation and increased AHR compared to lean asthma mice. The levels of cytokines examined in bronchoalveolar lavage fluid (BALF) revealed that the expressions of IL-4, 5, and 17 were elevated in the obese asthmatic group and decreased after pravastatin treatment, indicating that both the Th2 and Th17 pathways were stimulated by HFD-induced obesity and OVA challenge and suppressed by pravastatin treatment. Moreover, the serum leptin and adiponectin ratio was elevated only in obese asthmatic mice and decreased with pravastatin administration. Pravastatin successfully alleviated the airway inflammation of lung tissues and AHR in both obese and lean asthmatic mice, however, treatment with pravastatin had no effects on BALF cell counts and cytokines in lean asthma mice. In lung tissues, the phosphorylation of p38 MAPK was significantly decreased in lean as well as obese asthmatic mice. Pravastatin treatment in obese asthmatic mice suppressed allergic airway infiltration and AHR by inhibition of Th2 and Th17-associated signaling pathways, decreasing the leptin expression and downstream p38 MAPK signaling pathways. The effect on lean asthmatic mice was different, independent of airway cell counts and cytokines.
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http://dx.doi.org/10.1080/01902148.2019.1675807DOI Listing
May 2020

Clinical Characteristics and Outcomes of Patients with Culture-Negative Pyogenic Spondylitis according to Empiric Glycopeptide Use.

Infect Chemother 2019 Sep;51(3):274-283

Division of Infectious Disease, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea.

Background: The optimal choice of antibiotics is challenging in culture-negative pyogenic spondylitis (PS). The empiric use of glycopeptides is suggested depending on various risk factors, although clinical data are sparse. This study aimed to analyze the clinical characteristics and outcomes of patients with culture-negative PS and evaluate the effect of empiric glycopeptide use on clinical outcomes in these patients.

Materials And Methods: Data on the characteristics, treatment, and outcomes of 175 patients diagnosed with PS were retrospectively obtained from the electronic database of a tertiary referral hospital from 2009 to 2016. Patients with negative culture results were grouped by the duration of glycopeptide treatment: glycopeptide therapy <28 days (Group A) and glycopeptide therapy ≥28 days (Group B).

Results: Of 89 patients with negative culture results, 78 were included in the analysis (Group A, n = 66; Group B, n = 12). The mean age of patients with negative culture results was 65.5 years, and 52.6% were male. The median follow-up duration was 573 (interquartile range [IQR], 83 - 1,037) days. The duration of intravenous glycopeptide therapy was 0.0 (IQR, 0.0 - 0.0) days and 55.5 (IQR, 37.0 - 75.7) days for Groups A and B, respectively. Patients who used glycopeptide longer empirically (Group B) had more commonly undergone a previous spinal procedure, including surgery ( = 0.024). The length of hospitalization, erythrocyte sedimentation rate, and C-reactive protein level were significantly higher in Group B compared with those in Group A ( <0.001, <0.001, and = 0.006, respectively). Regarding treatment modalities, patients in Group B underwent surgery more frequently ( = 0.017). The duration of parenteral antibiotic treatment was longer in Group B ( <0.001). Recurrence was noted in 7 patients (9.0%), and the recurrence rate was not significantly different between the 2 groups (Group A, 5/66 [7.6%]; Group B, 2/12 [16.7%]; = 0.293).

Conclusion: The recurrence rate among patients with culture-negative PS was not different based on the duration of empiric glycopeptide use. However, considering the small sample size and heterogeneity of our study population, we suggest that it is reasonable to administer glycopeptide antibiotics in these patients depending on clinical risk factors. Further large-scale prospective studies are needed to obtain more evidence for appropriate antibiotic treatment.
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http://dx.doi.org/10.3947/ic.2019.51.3.274DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6779574PMC
September 2019

Clinical implications of discrepant results between genotypic MTBDR and phenotypic Löwenstein-Jensen method for isoniazid or rifampicin drug susceptibility tests in tuberculosis patients.

J Thorac Dis 2019 Feb;11(2):400-409

Department of Internal Medicine, St. Paul's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.

Background: The widespread use of molecular, genotypic drug susceptibility tests (DSTs) for antituberculosis (anti-TB) drugs has led to the dilemma of interpreting discordant results between genotypic and conventional, phenotypic DSTs. We investigated the clinical characteristics, including treatment patterns and outcomes, of TB patients with a genotype-phenotype discrepancy in susceptibility to isoniazid (INH) or rifampicin (RIF).

Methods: We retrospectively reviewed the medical records of TB patients who had results for 2 DSTs (genotypic method, MTBDR test for INH and RIF, and phenotypic method) treated between August 2010 and October 2016 in a tertiary university hospital.

Results: Among 1,069 TB patients, 63 (5.9%) had discrepant results for the 2 DSTs. Of the 57 multidrug-resistant (MDR) TB cases diagnosed by either DST, 18 (31.6%) showed discordant results for INH or RIF. The most frequent pattern of discordance was genotypic susceptibility with phenotypic resistance to INH. RIF-discordant subjects with genotypic resistance were more likely to have been exposed previously to anti-TB drugs and to have an MDR TB diagnosis and concurrent INH resistance. Forty-five of the 54 patients managed in our hospital (83.3%) had a favorable outcome with a mean treatment duration of 14.0 months. Ten of the 16 INH-discrepant patients with a genotypic mutation continued taking INH, but more than half patients in the RIF-discrepant group (8/14) with a genotypic mutation discontinued taking RIF.

Conclusions: Despite the low frequency, discordant results were obtained between the genotypic and phenotypic DSTs for INH or RIF, especially for patients with MDR TB or INH resistance. Furthermore, it seemed that RIF discrepancy with a genotypic mutation might have a greater impact on the clinical outcome than INH discrepancy.
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http://dx.doi.org/10.21037/jtd.2019.01.58DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6409268PMC
February 2019

Effect of nintedanib on airway inflammation in a mouse model of acute asthma.

J Asthma 2020 01 11;57(1):11-20. Epub 2019 Jan 11.

Division of Pulmonary, Allergy and Critical Care Medicine, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.

New treatments are needed for cases of asthma that are refractory to traditional therapies. In this study, we examined the effect of oral nintedanib, an intracellular inhibitor of tyrosine kinases, on airway hyper-responsiveness (AHR) and airway smooth muscle cells, using a mouse model of experimental asthma. Asthma was experimentally induced in mice via subcutaneous injection of ovalbumin (OVA). A group of saline-injected mice served as a control group. The OVA mice were then divided into four treatment groups according to the dose of nintedanib. AHR was examined via exposure to vaporized methacholine. Airway inflammation was assessed via bronchoalveolar lavage fluid (BALF) cell counts and Th2 cytokine concentrations. Baseline levels of AHR and airway inflammation were higher in OVA mice than in the control group. Treatment with nintedanib lowered AHR, BALF cell counts and BALF cytokine levels in a dose-dependent fashion. The effect of nintedanib was comparable to that of dexamethasone. In particular, treatment with nintedanib lowered the expression of transforming growth factor-β1 and inhibited the expression and phosphorylation of platelet-derived growth factor receptor-β, vascular endothelial growth factor receptor 1 (VEGFR1), VEGFR2, fibroblast growth factor receptor 2 (FGFR2), FGFR3, and extracellular signal-regulated kinase. Nintedanib lowered AHR and the expression of factors associated with airway inflammation and remodeling in a mouse model of experimental asthma. Our results suggest that nintedanib may be useful in the treatment of asthma.
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http://dx.doi.org/10.1080/02770903.2018.1544641DOI Listing
January 2020

Expression of Muscarinic Receptors and the Effect of Tiotropium Bromide in Aged Mouse Model of Chronic Asthma.

Tuberc Respir Dis (Seoul) 2019 Jan;82(1):71-80

Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea.

Background: Efficacy and safety of tiotropium bromide, a muscarinic receptor antagonist, in treatment of asthma have been reported. However, its effect on airway remodeling in chronic asthma of the elderly has not been clearly verified. The objective of this study was to investigate the effect of tiotropium and expression of muscarinic receptors as its related mechanism in an aged mouse model of chronic asthma with airway remodeling.

Methods: BALB/c female mice age 6 weeks, 9 and 15 months were sensitized and challenged with ovalbumin (OVA) for three months. Tiotropium bromide was administered during the challenge period. Airway hyperresponsiveness (AHR) and pulmonary inflammation were measured. Parameters of airway remodeling, and expression levels of M₂ and M₃ receptors were examined.

Results: Total cell with eosinophils, increased in the OVA groups by age, was decreased significantly after treatment with tiotropium bromide, particularly in the age group of 15 months. AHR and levels of interleukin (IL)-4, IL-5, and IL-13 were decreased, after tiotropium administration. In old aged group of 9- and 15-months-treated groups, hydroxyproline contents and levels of α-smooth muscle actin were attenuated. Tiotropium enhanced the expression of M₂ but decreased expression of M₃ in all aged groups of OVA.

Conclusion: Tiotropium bromide had anti-inflammatory and anti-remodeling effects in an aged mouse model of chronic asthma. Its effects seemed to be partly mediated by modulating expression M₃ and M₂ muscarinic receptors. Tiotropium may be a beneficial treatment option for the elderly with airway remodeling of chronic asthma.
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http://dx.doi.org/10.4046/trd.2018.0049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6304325PMC
January 2019

TRPV1 Blocking Alleviates Airway Inflammation and Remodeling in a Chronic Asthma Murine Model.

Allergy Asthma Immunol Res 2018 May;10(3):216-224

Division of Pulmonology, Department of Internal Medicine, Seoul St. Mary's Hospital, The Catholic University of Korea College of Medicine, Seoul, Korea.

Purpose: Asthma is a chronic inflammatory airway disease characterized by airway hyperresponsiveness (AHR), inflammation, and remodeling. There is emerging interest in the involvement of the transient receptor potential vanilloid 1 (TRPV1) channel in the pathophysiology of asthma. This study examined whether TRPV1 antagonism alleviates asthma features in a murine model of chronic asthma.

Methods: BALB/c mice were sensitized to and challenged by ovalbumin to develop chronic asthma. Capsazepine (TRPV1 antagonist) or TRPV1 small interfering RNA (siRNA) was administered in the treatment group to evaluate the effect of TPV1 antagonism on AHR, airway inflammation, and remodeling.

Results: The mice displayed increased AHR, airway inflammation, and remodeling. Treatment with capsazepine or TRPV1 siRNA reduced AHR to methacholine and airway inflammation. Type 2 T helper (Th2) cytokines (interleukin [IL]-4, IL-5, and IL-13) were reduced and epithelial cell-derived cytokines (thymic stromal lymphopoietin [TSLP], IL-33, and IL-25), which regulate Th2 cytokine-associated inflammation, were also reduced. Airway remodeling characterized by goblet cell hyperplasia, increased α-smooth muscle action, and collagen deposition was also alleviated by both treatments.

Conclusions: Treatment directed at TRPV1 significantly alleviated AHR, airway inflammation, and remodeling in a chronic asthma murine model. The TRPV1 receptor can be a potential drug target for chronic bronchial asthma.
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http://dx.doi.org/10.4168/aair.2018.10.3.216DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5911440PMC
May 2018

Effect of the anti-IL-17 antibody on allergic inflammation in an obesity-related asthma model.

Korean J Intern Med 2018 Nov 19;33(6):1210-1223. Epub 2018 Apr 19.

Division of Pulmonary, Allergy and Critical Care Medicine, Department of Internal Medicine, College of Medicine, Seoul St. Mary's Hospital, The Catholic University of Korea, Seoul, Korea.

Background/aims: The co-occurrence of obesity aggravates asthma symptoms. Diet-induced obesity increases helper T cell (TH) 17 cell differentiation in adipose tissue and the spleen. The 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor pravastatin can potentially be used to treat asthma in obese patients by inhibiting interleukin 17 (IL-17) expression. This study investigated the combined effects of pravastatin and anti-IL-17 antibody treatment on allergic inflammation in a mouse model of obesity-related asthma.

Methods: High-fat diet (HFD)-induced obesity was induced in C57BL/6 mice with or without ovalbumin (OVA) sensitization and challenge. Mice were administered the anti-IL-17 antibody, pravastatin, or both, and pathophysiological and immunological responses were analyzed.

Results: HFD exacerbated allergic airway inflammation in the bronchoalveolar lavage fluid of HFD-OVA mice as compared to OVA mice. Blockading of the IL-17 in the HFD-OVA mice decreased airway hyper-responsiveness (AHR) and airway inflammation compared to the HFD-OVA mice. Moreover, the administration of the anti-IL-17 antibody decreased the leptin/adiponectin ratio in the HFD-OVA but not the OVA mice. Co-administration of pravastatin and anti-IL-17 inhibited airway inflammation and AHR, decreased goblet cell numbers, and increased adipokine levels in obese asthmatic mice.

Conclusion: These results suggest that the IL-17-leptin/adiponectin axis plays a key role in airway inflammation in obesity-related asthma. Our findings suggest a potential new treatment for IL-17 as a target that may benefit obesity-related asthma patients who respond poorly to typical asthma medications.
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http://dx.doi.org/10.3904/kjim.2017.207DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6234391PMC
November 2018

The leukotriene receptor antagonist pranlukast attenuates airway remodeling by suppressing TGF-β signaling.

Pulm Pharmacol Ther 2018 02 13;48:5-14. Epub 2017 Oct 13.

Division of Allergy and Pulmonary Medicine, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea. Electronic address:

Background/objective: Asthma is a chronic airway disease characterized by airway eosinophilic inflammation and remodeling, which are associated with a loss in lung function. Although both contribute significantly to asthma pathogenesis, mechanistic studies and drug discovery have focused on inflammatory targets. In this study, we investigated the effect of the leukotriene receptor antagonist pranlukast on allergic airway inflammation and remodeling in vivo and in vitro.

Method: Four groups of female BALB/c mice (control; ovalbumin [OVA]-sensitized and -challenged; dimethyl sulfoxide [DMSO]-treated OVA; and pranlukast-treated OVA) were examined. Lung pathology, cytokine production, and airway hyperresponsiveness (AHR) measurements were compared among these groups. A human fetal lung fibroblast HFL-1 cell line was used in the peribranchial fibrosis analysis.

Results: OVA-sensitized and -challenged mice exhibited allergic airway inflammation and significant increases in Th2 cytokines. Pranlukast-treated mice showed significant attenuation of allergic airway inflammation. The pranlukast treatment decreased AHR and attenuated airway remodeling to goblet cell hyperplasia, collagen deposition, α-smooth muscle actin expression, and pro-fibrotic gene expression. We further demonstrated that pranlukast not only inhibited transforming growth factor-beta 1 (TGF-β1)-induced Smad signaling in human fetal lung fibroblast cells but also simultaneously reduced collagen synthesis and pro-fibrotic gene expression.

Conclusions: The leukotriene receptor antagonist pranlukast can reduce airway inflammation and remodeling by inhibiting TGF-β/Smad signaling in an OVA-sensitized and -challenged asthma mouse model, thus suppressing AHR.
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http://dx.doi.org/10.1016/j.pupt.2017.10.007DOI Listing
February 2018

Effect of nintedanib on airway inflammation and remodeling in a murine chronic asthma model.

Exp Lung Res 2017 May - Jun;43(4-5):187-196. Epub 2017 Jul 11.

b Division of Pulmonary, Allergy and Critical Care Medicine, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine , The Catholic University of Korea , Seoul , Republic of Korea.

Introduction: Nintedanib is a multi-tyrosine kinase receptor inhibitor recently approved for treatment of idiopathic pulmonary fibrosis. Although angiogenesis is a key process involved in airway structural changes in patients with bronchial asthma, the effect of nintedanib targeting the angiokinase pathway on airway inflammation and remodeling has not been evaluated.

Methods: We used a 3-month ovalbumin (OVA) challenge mouse model of airway remodeling. Nintedanib was orally administrated during the challenge period, and the effects were examined based on the percentage of airway inflammatory cells, airway hyper-reactivity (AHR), peribronchial goblet cell hyperplasia, total lung collagen and smooth muscle area. The expression of growth factor receptors was analyzed in mice lung tissues.

Results: The OVA challenged group showed a significant increase in airway eosinophilic inflammation, elevated Th2 cytokines, AHR, and airway remodeling compared to those in the control group. The airway remodeling process, as evaluated by goblet cell hyperplasia, total lung collagen level, and airway smooth muscle area, was suppressed by nintedanib compared to that by OVA. Nintedanib effectively suppressed the phosphorylation of vascular endothelial growth factor/ platelet derived growth factor subunit2/fibroblast growth factor3 receptors in the mice lung.

Conclusions: Nintedanib effectively ameliorated airway inflammation and remodeling in an OVA-induced chronic asthma model. These results suggest that nintedanib could be a new treatment agent targeting airway remodeling in patients with severe asthma.
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http://dx.doi.org/10.1080/01902148.2017.1339141DOI Listing
June 2018

Inhibition of MicroRNA-21 by an antagomir ameliorates allergic inflammation in a mouse model of asthma.

Exp Lung Res 2017 04 5;43(3):109-119. Epub 2017 Apr 5.

a Division of Pulmonary, Allergy and Critical Care Medicine, Department of Internal Medicine , The Catholic University of Korea , Seoul , South Korea.

Aim Of The Study: MicroRNA-21 (miR-21) is up-regulated during allergic airway inflammation, reflecting a Th2 immune response. We investigated the effects of an miR-21 antagomir and its mechanism of action in a mouse model of acute bronchial asthma.

Materials And Methods: BALB/c mice were sensitized and challenged with ovalbumin (OVA). The anti-miR-21 antagomir was administered by intranasal inhalation from the day of sensitization. Changes in cell counts, Th2 cytokine levels in bronchoalveolar (BAL) fluid, and airway hyper-responsiveness (AHR) were examined. Histopathological changes and expression levels of miR-21 in lung tissues were analyzed. The mechanism of action of the antagomir was investigated by counting CD4/CD8 T cells in splenocytes and by measuring the expression levels of transcription factors associated with T cell polarization.

Results: MiR-21 expression was selectively down-regulated in the lung tissues of mice treated with anti-miR-21. The antagomir suppressed AHR compared with that of the OVA-challenged and scrambled RNA-treated groups. It also reduced the total cell and eosinophil counts in BAL fluid and the levels of Th2 cytokines, including IL-4, IL-5, and IL-13. The direct target of miR-21, IL-12p35, was induced in the antagomir-treated group, decreasing the CD4/CD8 T cell proportions in splenocytes. The levels of transcription factors involved in the Th2-signaling pathway were reduced in lung tissues on treatment with the antagomir.

Conclusions: The miR-21 antagomir suppresses the development of allergic airway inflammation in a mouse model of acute bronchial asthma, inhibiting Th2 activation. These results suggest that this antagomir might be useful for treating bronchial asthma.
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http://dx.doi.org/10.1080/01902148.2017.1304465DOI Listing
April 2017

HuR represses Wnt/β-catenin-mediated transcriptional activity by promoting cytoplasmic localization of β-catenin.

Biochem Biophys Res Commun 2015 Jan 19;457(1):65-70. Epub 2014 Dec 19.

Department of Molecular Biology, Dankook University, Yongin, Gyeonggi-do 448-701, Republic of Korea. Electronic address:

β-Catenin is the key transcriptional activator of canonical Wnt signaling in the nucleus; thus, nuclear accumulation of β-catenin is a critical step for expressing target genes. β-Catenin accumulates in the nucleus of cancer cells where it activates oncogenic target genes. Hu antigen R (HuR) is a RNA binding protein that regulates multiple post-transcriptional processes including RNA stability. Thus, cytoplasmic HuR protein may be involved in tumorigenesis by stabilizing oncogenic transcripts, but the molecular mechanism remains unclear. Here, we observed that Wnt/β-catenin signaling induced export of the HuR protein, whereas HuR overexpression promoted accumulation of the β-catenin protein in the cytoplasm. Thus, Wnt/β-catenin-mediated transcriptional activity in the nucleus was reduced by overexpressing HuR. These results suggest novel and uncharacterized cytoplasmic β-catenin functions related to HuR-mediated RNA metabolism in cancer cells.
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http://dx.doi.org/10.1016/j.bbrc.2014.12.052DOI Listing
January 2015

The effectiveness of endoscopic radiofrequency denervation of medial branch for treatment of chronic low back pain.

J Korean Neurosurg Soc 2014 Oct 31;56(4):338-43. Epub 2014 Oct 31.

Department of Neurosurgery, Seoul St. Mary's Hospital, The Catholic University of Korea College of Medicine, Seoul, Korea.

Objective: The aim of this study is to evaluate the clinical results of endoscopic radiofrequency ablation of medial branch in patients with chronic low back pain originating from facet joints.

Methods: Between October 2010 and December 2013, 52 consecutive patients had suffering from chronic low back pain had undergone endoscopic radiofrequency denervation of medial branch of dorsal ramus. The clinical outcomes of these 52 patients were reviewed retrospectively. Preoperative and postoperative Visual Analogue Scale (VAS) and Korean version of Oswestry Disability Index (K-ODI), and patients' satisfaction with the procedure were assessed.

Results: The pain scores on the VAS for back pain had improved significantly from a preoperative mean of 7.1 to a postoperative mean of 2 at the last follow-up (p<0.001). The clinical outcomes based on the K-ODI had also improved significantly from a preoperative mean of 26.5% to postoperative mean of 7.7% at the last follow-up (p<0.001). 80% of patients were satisfied with the procedure. There were no complications associated with the procedure.

Conclusion: Our preliminary results demonstrate that endoscopic radiofrequency denervation of medial branch could be an effective alternative treatment modality for chronic back pain originating from facet joints that provides long-term pain relief.
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http://dx.doi.org/10.3340/jkns.2014.56.4.338DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4219193PMC
October 2014

High-efficiency blue phosphorescent organic light-emitting diodes using a carbazole and carboline-based host material.

Chem Commun (Camb) 2013 Aug;49(60):6788-90

Department of Chemistry, Research Institute for Natural Sciences, Korea University, 5 Anam-dong, Sungbuk-Gu, Seoul, 136-701 Republic of Korea.

A novel bipolar host 9-(4-(9H-pyrido[2,3-b]indol-9-yl)phenyl)-9H-3,9'-bicarbazole (pBCb2Cz) was prepared for high efficiency blue phosphorescent organic light-emitting diodes (PhOLEDs), a high triplet energy (ET) material, employing electron-deficient α-carboline. pBCb2Cz (ET = 2.93 eV) was effective as a host material for FIrpic- and FCNIrpic-based blue PhOLEDs, and highest quantum efficiencies of 23.0 and 16.2%, respectively, were achieved.
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http://dx.doi.org/10.1039/c3cc42569jDOI Listing
August 2013

Activation-free printed carbon nanotube field emitters.

Nanotechnology 2011 Oct 29;22(43):435601. Epub 2011 Sep 29.

Advanced Materials Laboratory, Samsung Advanced Institute of Technology, Giheung-gu, Yongin-si, Gyeonggi-do 446-712, Korea.

When a carbon nanotube paste is formulated based on highly functional hyperbranched polymers such as dipentaerythritol hexaacrylate, the volume shrinkage during thermal curing builds up internal stress that generates microcrack patterns on the printed surface. The nanotubes exposed in the cracks emit electrons successfully at such an extremely low electric field as 0.5 V µm( - 1), and reach 25.5 mA cm( - 2) of current density at 2 Vµm( - 1) from an optimized paste concerning mainly the size and spatial uniformity of the crack. In addition to the superior field emission properties with low manufacturing cost, this activation-free technology can provide a minimized nanohazard in the device fabrication process, compared to those conventional activation technologies developing serious nanoflakes by using destructive methods.
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http://dx.doi.org/10.1088/0957-4484/22/43/435601DOI Listing
October 2011

Highly sensitive phototransistor with crystalline microribbons from new π-extended pyrene derivative via solution-phase self-assembly.

Chem Commun (Camb) 2011 Aug 16;47(31):8907-9. Epub 2011 Jun 16.

Department of Chemistry, Research Institute for Natural Sciences, Korea University, 5 Anam-dong, Sungbuk-gu, Seoul, 136-701 Korea.

A new pyrene-cored π-conjugated molecule has been synthesized through Sonogashira coupling reaction. The single-crystalline microribbon-based FET exhibited the highest mobility of 0.7 cm(2) V(-1) s(-1) (I(on)/I(off) > 10(6)). Single-crystalline microribbons were employed to operate in an organic phototransistor (OPT) under very low light intensity (I = 5.6 μW cm(-2)).
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http://dx.doi.org/10.1039/c1cc11589hDOI Listing
August 2011

Highly photosensitive J-aggregated single-crystalline organic transistors.

Adv Mater 2011 Jul 19;23(27):3095-9. Epub 2011 May 19.

Dept. of Chemistry, Research Institute for Natural Sciences, Korea University, Anam-dong, Sungbuk-gu, Seoul, Korea.

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http://dx.doi.org/10.1002/adma.201100944DOI Listing
July 2011

Semiconducting 2,6,9,10-tetrakis(phenylethynyl)anthracene derivatives: effect of substitution positions on molecular energies.

Org Lett 2011 Apr 16;13(8):1948-51. Epub 2011 Mar 16.

Department of Chemistry, College of Science, Research Institute for Natural Sciences, Korea University, 5 Anam-dong, Sungbuk-gu, Seoul 136-701, Korea.

2,6-Bis((4-hexylphenyl)ethynyl)-9,10-bis(phenylethynyl)anthracene, 4, and 9,10-bis((4-hexylphenyl)ethynyl)-2,6-bis (phenyl ethynyl)anthracene, 5, have been synthesized to study their electronic and photophysical properties. It should be noted that the difference between these compounds is the substitution position of 1-ethynyl-4-hexylbenzene groups into an anthracene ring. In particular, substitution in the 9,10-positions of the anthracene ring enhanced J-aggregated intermolecular interactions. Since 5 has a lower bandgap energy and more compact film morphology, it exhibited higher hole mobility (∼0.27 cm(2) V(-1) s(-1)) in thin-film transistor devices.
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http://dx.doi.org/10.1021/ol200299sDOI Listing
April 2011

The RNA aptamer disrupts protein-protein interaction between beta-catenin and nuclear factor-kappaB p50 and regulates the expression of C-reactive protein.

FEBS Lett 2009 May 7;583(9):1415-21. Epub 2009 Apr 7.

National Research Laboratory for RNA Cell Biology, BK21 Graduate Program for RNA Biology and Department of Molecular Biology, Dankook University, 126, Yongin-si, Gyeonggi-do 448-701, Republic of Korea.

Transcription is activated by signal-induced protein-protein interaction between transcription factors on regulatory elements positioned near their target genes. Here, we tested the utility of the beta-catenin binding RNA aptamer as a tool for studying protein-protein interaction within transcription complex and for modulating expression of a target gene. The RNA aptamer bound Armadillo repeats of beta-catenin and was effective in disrupting protein-protein interaction between beta-catenin and nuclear factor-kappaB (NF-kappaB) p50. In addition, the RNA aptamer effectively reduced tumor necrosis factor-alpha induced transcription from the promoter of C-reactive protein regulated by beta-catenin and NF-kappaB p50. Taken together, beta-catenin binding RNA aptamer was an effective regulator of beta-catenin and NF-kappaB p50 mediated transcription.
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http://dx.doi.org/10.1016/j.febslet.2009.04.002DOI Listing
May 2009

Emerging roles of RNA and RNA-binding protein network in cancer cells.

BMB Rep 2009 Mar;42(3):125-30

National Research Lab for RNA Cell Biology, BK21 Graduate Program for RNA Biology and Department of Molecular Biology, Dankook University, Gyeonggi-do 448-701, Republic of Korea.

Recent advances in RNA biology reveal unexpected diversity and complexity of cellular RNA metabolism. RNA-binding proteins (RBPs) are essential players in RNA metabolism, regulating RNA splicing, transport, surveillance, decay and translation. Aberrant expression of RBPs affects many steps of RNA metabolism, significantly altering expression of RNA. Thus, altered expression and dysfuncting of RBPs are implicated in the development of various diseases including cancer. In this minireview, we briefly describe emerging roles of RBPs as a global coordinator of post-transcriptional steps and altered RBP as a global generator of cancer related RNA alternative splicing. Identification and characterization of the RNA-RBP network would expand the scope of cellular RNA metabolism and provide novel anti-cancer therapeutic targets based on cancer specific RNA-RBP interaction.
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http://dx.doi.org/10.5483/bmbrep.2009.42.3.125DOI Listing
March 2009

beta-catenin regulates multiple steps of RNA metabolism as revealed by the RNA aptamer in colon cancer cells.

Cancer Res 2007 Oct;67(19):9315-21

Department of Molecular Biology, BK21 Graduate Program for RNA Biology, Institute of Nanosensor and Biotechnology, Dankook University Seoul, Republic of Korea.

Nuclear beta-catenin forms a transcription complex with TCF-4, which is implicated in colon cancer development and progression. Recently, we and others have shown that beta-catenin could be a regulator of RNA splicing and it also stabilizes the cyclooxygenase-2 (COX-2) mRNA. Here, we further explored the role of beta-catenin in the RNA metabolism in colon cancer cells. To specifically modulate the subcellular functions of beta-catenin, we expressed the RNA aptamer in the form of RNA intramers with unique cellular localizations. The nucleus-expressed RNA intramer proved to be effective in reducing the protein-protein interaction between beta-catenin and TCF-4, thus shown to be a specific regulator of beta-catenin-activated transcription. It could also regulate the alternative splicing of E1A minigene in diverse colon cancer cell lines. In addition, we tested whether beta-catenin could stabilize any other mRNAs and found that cyclin D1 mRNA was also bound and stabilized by beta-catenin. Significantly, the cytoplasm-expressed RNA intramer reverted the beta-catenin-induced COX-2 and cyclin D1 mRNA stabilization. We show here that beta-catenin regulated multiple steps of RNA metabolism in colon cancer cells and might be the protein factor coordinating RNA metabolism. We suggest that the RNA intramers could provide useful ways for inhibiting beta-catenin-mediated transcription and RNA metabolism, which might further enhance the antitumorigenic effects of these molecules in colon cancer cells.
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http://dx.doi.org/10.1158/0008-5472.CAN-07-1128DOI Listing
October 2007

Beta-catenin binds to the downstream region and regulates the expression C-reactive protein gene.

Nucleic Acids Res 2007 17;35(16):5511-9. Epub 2007 Aug 17.

Department of Molecular Biology, BK21 Graduate Program for RNA Biology, Institute of Nanosensor and Biotechnology, Dankook University, Seoul 140-714, Republic of Korea.

C-Reactive protein (CRP) is a major acute-phase response protein, which is activated by various cytokines. We investigated the mechanism of TNF-alpha-induced CRP expression and found that the p50 subunit of NF-kappaB was responsible for the transcriptional activation of CRP. Since the p50 protein acts as a positive regulator of CRP expression without an inherent transactivation domain, we looked for an interaction partner that could provide p50 with such a domain. We found that beta-catenin enhanced the expression of a CRP mRNA in concert with p50 subunit. Protein-protein interaction between p50 and beta-catenin was important for CRP expression and their interactions to CRP promoter were induced after TNF-a treatment. Since gene expression depends upon the proximity of promoters and distal regulatory sites, we explored the long-range genomic interaction at the CRP locus by chromosome conformation capture (3C). We identified a binding site for beta-catenin in the downstream of CRP gene by 3C and confirmed TNF-alpha-induced association of beta-catenin and p50 by chromatin immunoprecipitation and co-immunoprecipitation assays. Our findings provide evidence that transcription of the CRP gene depends upon p50 and beta-catenin proteins, which is accompanied by close proximity between promoter and the downstream region of CRP gene.
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http://dx.doi.org/10.1093/nar/gkm547DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2018623PMC
September 2007

A graph-theoretic modeling on GO space for biological interpretation of gene clusters.

Bioinformatics 2004 Feb 22;20(3):381-8. Epub 2004 Jan 22.

Bioinformatics Unit, ISTECH Inc., No 704, Hyundai Town Vill 848-1, Janghang-dong, Ilsan-gu, Goyang city, Gyunggido, 411-380, Republic of Korea.

Motivation: With the advent of DNA microarray technologies, the parallel quantification of genome-wide transcriptions has been a great opportunity to systematically understand the complicated biological phenomena. Amidst the enthusiastic investigations into the intricate gene expression data, clustering methods have been the useful tools to uncover the meaningful patterns hidden in those data. The mathematical techniques, however, entirely based on the numerical expression data, do not show biologically relevant information on the clustering results.

Results: We present a novel methodology for biological interpretation of gene clusters. Our graph theoretic algorithm extracts common biological attributes of the genes within a cluster or a group of interest through the modified structure of gene ontology (GO) called GO tree. After genes are annotated with GO terms, the hierarchical nature of GO terms is used to find the representative biological meanings of the gene clusters. In addition, the biological significance of gene clusters can be assessed quantitatively by defining a distance function on the GO tree. Our approach has a complementary meaning to many statistical clustering techniques; we can see clustering problems from a different viewpoint by use of biological ontology. We applied this algorithm to the well-known data set and successfully obtained the biological features of the gene clusters with the quantitative biological assessment of clustering quality through GO Biological Process.
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http://dx.doi.org/10.1093/bioinformatics/btg420DOI Listing
February 2004

Identification of a compound that directly stimulates phospholipase C activity.

Mol Pharmacol 2003 May;63(5):1043-50

Medical Research Center for Cancer Molecular Therapy and Department of Biochemistry, College of Medicine, Dong-A University, Busan, Korea.

Phosphoinositide-specific phospholipase C (PLC) plays a pivotal role in the signal transduction of various cellular responses. However, although it is undeniably important that modulators of PLC activity be identified, no direct PLC activity modulator has been identified until now. In this study, by screening more than 10,000 different compounds in human neutrophils, we identified a compound that strongly enhances superoxide-generating activity, which is well known to be PLC-dependent. The active compound 2,4,6-trimethyl-N-(meta-3-trifluoromethyl-phenyl)-benzenesulfonamide (m-3M3FBS) stimulated a transient intracellular calcium concentration ([Ca(2+)](i)) increase in neutrophils. Moreover, m-3M3FBS stimulated the formation of inositol phosphates in U937 cells, indicating that it stimulates PLC activity. The compound showed no cell-type specificity in terms of [Ca(2+)](i) increase in the various cell lines including leukocytes, fibroblasts, and neuronal cells. We also ruled out the possible involvement of heterotrimeric G proteins in m-3M3FBS-stimulated signaling by confirming the following: 1) pertussis toxin does not inhibit m-3M3FBS-induced [Ca(2+)](i) increase; 2) m-3M3FBS does not stimulate cyclic AMP generation; and 3) the inhibition of G(q) by the regulator of G protein-signaling 2 does not affect the m-3M3FBS-induced [Ca(2+)](i) increase. We also observed that m-3M3FBS stimulated PLC activity in vitro. The purified isoforms of PLC that were tested (i.e., beta2, beta3, gamma1, gamma2, and delta1) were activated by m-3M3FBS and showed no isoform specificity. Taken together, these results demonstrate that m-3M3FBS modulates neutrophil functions by directly activating PLC. Because m-3M3FBS is the first compound known to directly activate PLC, it should prove useful in the study of the basic molecular mechanisms of PLC activation and PLC-mediated cell signaling.
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http://dx.doi.org/10.1124/mol.63.5.1043DOI Listing
May 2003
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